Research School of Biology, Australian National University, Canberra, Australia.
J Phys Chem B. 2012 Feb 16;116(6):1933-41. doi: 10.1021/jp210105f. Epub 2012 Feb 7.
Using a novel rigid body Brownian dynamics algorithm, we investigate how a spherically asymmetrical polyamine molecule, a branched analogue of spermine, interacts with the external vestibule of the voltage-gated potassium channel, Kv1.2. Simulations reveal that the blocker, with a charge of +4e, inserts one of its charged amine groups into the selectivity filter, while another forms a salt bridge with an aspartate residue located just outside the entrance of the pore. This binding mode mimics features of the binding of polypeptides such as the scorpion venom charybdotoxin to the channel. The potential of mean force constructed with Brownian dynamics is a reasonable match to that obtained from molecular dynamics simulations, with dissociation constants of 4.7 and 22 μM, respectively. The current-voltage relationships obtained with and without a blocker in the external reservoir show that the inward current is severely attenuated by the presence of the blocker, whereas the outward current is only moderately reduced. The computational molecular modeling technique we introduce here can provide detailed insights into ligand-channel interactions and can be used for rapidly screening potential blocker molecules.
我们使用新颖的刚性布朗动力学算法研究了具有球形不对称结构的聚胺分子（精胺的支链类似物）如何与电压门控钾通道 Kv1.2 的外部前庭相互作用。模拟结果表明，带正电荷 4e 的阻滞剂将其带电荷的胺基之一插入选择性过滤器，而另一个与位于孔入口外的天冬氨酸残基形成盐桥。这种结合模式模拟了多肽（如蝎子毒液 charybdotoxin）与通道结合的特征。布朗动力学构建的平均力势能与分子动力学模拟得到的结果非常吻合，解离常数分别为 4.7 和 22 μM。在外部储库中存在和不存在阻滞剂的情况下获得的电流-电压关系表明，阻滞剂的存在严重减弱了内向电流，而外向电流仅适度降低。我们在这里引入的计算分子建模技术可以深入了解配体-通道相互作用，并可用于快速筛选潜在的阻滞剂分子。
